There are a great many drugs in use today whose major activation or detoxification pathways involve pathways catalyzed by mammalian tissue carboxylesterases or carboxylamidases. Many of the commonly used organophosphate insecticides cause selective inhibition of tissue esterases and amidases without any visible signs of toxicity. Thus, presumably nontoxic exposures to organophosphates may be sufficient to inhibit tissue esterases and amidases which may be critical for the hydrolysis of certain ester and amide drugs, thereby altering the therapeutic effectivess and/or toxicity of those drugs. The proposed research will investigate the relationship between inhibition of tissue esterases and amidases and alterations in the metabolism and toxicity of ester and amide drugs which may occur after exposure to organophosphate insecticides. The primary approach to be employed in investigating this relationship will be to conduct dose and time response studies of the effects of organophosphates, administered in vivo, on the acute toxicity and metabolism, in vitro and in vivo, of ester and amide drugs. Several ester and amide, drug and nondrug substrates will be compared in enzymatic assays to determine which substrate(s) might be most useful in predictive testing for toxic interactions during safety evaluation of organophosphate insecticides. It is intended that the proposed research will contribute to the understanding and predictability of toxicologic interactions between drugs and insecticides. In addition, it will provide information which will help determine the degree of drug esterase and amidase inhibition which can be tolerated without alteration in drug toxicity. The drugs to be included in this study have been selected because they are currently used in humans and may therefore provide a basis for comparison of the results of this research with future controlled tests in organophosphate exposed humans.